Verapamil, or 5-(3,4-dimethoxyphenylethyl)methyl-amino-2-(3,4-dimethoxyphenyl)-2-isopropyl valeronitrile has been known for more than 20 years and its synthesis is described in Belgian Pat. No. 615 816 corresponding to the Dengel U.S. Pat. No. 3,261,859.

The hydrochloride of verapamil is used in medicine for its remarkable antagonistic properties against intracellular penetration of calcium. It is an important drug for the treatment of angina pectoris when the attack is associated with a coronary spasm and beta-adrenolytic products such as propanolol, timolol, atenolol and pindolol are liable to have undesirable effects. It is also useful in the treatment of hypertension and cardiac arrythmia. It is known to the man of the art that the pharmacological action of verapamil is proportional to its concentration in the plasma (Br. J. Clin. Pharmac. (1981), 12, 397-400) and that the optimum therapeutic range extends from 100 ng/ml to 400 ng/ml of plasma.
Verapamil is presently in clinical use as the racemate and is used extensively for the treatment of hypertension. The opposite enantiomers of verapamil have different biological activities. The (S)-enantiomer (levoverapamil) has the majority of the calcium channel antagonist activity (DE-A-2059923) whilst the (R)-enantiomer (dextroverapamil) differs in having sodium channel and other cell-pump actions in addition to higher bioavailability, with slower clearance rate. Verapamil is a known Ca channel blocker and is a competitive inhibitor of P-glycoprotein. Processes for the preparation of verapamil are disclosed in several prior art documents such as U.S. Pat. No. 3,261,859 and U.S. Pat. No. 4,418,017. Verapamil obtained according to the procedure disclosed in these prior art documents involves the formation of a dimer along with various O-desmethyl and N-desmethyl derivatives of verapamil as impurities, which reduces the purity of verapamil and also lowers the yield due to repeated purification by multiple and elaborate crystallization processes.
The yield is reduced during the process of repeated purification. Therefore a need was felt to develop an efficient process of preparation of verapamil and further its hydrochloride, wherein the impurities formed during the process can be easily separated out without the requirement for repeated crystallization of the final product, thereby making the process of the present invention simple, efficient, cost-effective and industrially feasible.
The object of this invention is to provide an alternative process for the preparation of verapamil hydrochloride, the compound represented by Formula I herein, which process of the present invention will allow efficient large-scale synthesis by overcoming the drawbacks of the conventional technique involving formation of impurities.